1. Field
This disclosure is concerned generally with the use of antibiotics to treat infections of medically significant fungi. Specifically, the disclosure is concerned with the use of a class of antibiotics known as nikkomycins to treat infections of dimorphic and highly chitinous (more than 10% by weight chitin) fungi in mammals.
2. Prior Art
Compounds inhibitory to the synthesis of fungal cell wall material (synthase inhibitors) have been reported recently to have demonstrable effects against fungi of agricultural importance (U.S. Pat. Nos. 4,315,922 and 4,158,608). See also U.S. Pat. Nos. 4,585,761 and 4,552,954 for descriptions of the preparation and purification of such compounds. The agents mentioned in the cited patents, nikkomycins, together with similar agents known as polyoxins, are known to act by interfering with the synthesis of chitin in the cell walls of fungi. Because fungi of medical importance to humans also have varying amounts of chitin in their cell walls, experiments have been conducted to determine if the chitin synthase inhibitors are capable of inhibiting the growth of such fungi (Hector and Pappagianis, J. Bacteriol. 154:488-498, 1983, and Hector and Braun, Antimicrobial Agents Chemother, 29:389-394, 1986). In earlier work, certain fungi such as Candida albicans were reported to be insensitive to chitin synthase inhibitors (see Naider et al, Antimicrobial Agents Chemother. 24:787-796, 1983). Subsequently, C. albicans was found to be more sensitive to nikkomycins than polyoxins (see Yadan et al, J. Bacteriol. 160:884-888, 1984) but the concentrations necessary for killing that yeast would (for toxicity reasons) preclude their use as chemotherapeutic agents for yeast infections (see Hector and Braun, Antimicrobial Agents Chemother., 29:389-394, 1986).
Quite surprisingly, I have now found that nikkomycin compounds are efficacious in treating fungal infections if the fungal agents are highly chitinous in the parasitic phase. Although the results described below were surprising, it is thought that they may be based on the difference in chitin content in the cell walls of the fungi (see, for example, Chattaway et al, J. Gen. Microbiol. 51:367-376, 1967, where C. albicans is reported to contain less than 1% by weight chitin in the cell wall).
As reported below, data from in vivo and in vitro studies using Coccidioides immitis dimorphic fungi show that nikkomycin compounds are efficacious in treating infections of such fungi.